On October 24, 2017 GT Biopharma Inc. (OTCQB: GTBP and Euronext Paris GTBP.PA) reported the FDA has accepted the transfer of IND 136205 Change of Sponsor from the University of Minnesota to GT Biopharma for a commercial IND of OXS-3550 (anti-CD16-IL-15-anti-CD33); a first of its kind, single-chain, tri-specific NK cell engager (TriKE) (Press release, GT Biopharma , OCT 24, 2017, View Source [SID1234539537]).

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OXS-3550 TriKE technology was developed by researchers at the University of Minnesota Masonic Cancer Center. As demonstrated in non-clinical models, this targeted immunotherapy directs immune cells to kill cancer cells while diminishing drug-related toxicity.

Several months ago, the GT Biopharma TriKE platform technology received funding from the University of Minnesota’s National Institution of Health (NIH) REACH award. This award is given by the NIH to support technology that is promising for commercial success.

The TriKE platform technology can be viewed as a protein version of CAR-T. However, unlike traditional CAR-T platforms like Kite Pharma (KITE) and Juno Therapeutics (JUNO), TriKEs are not an expensive cell therapy currently only available to treat liquid tumors. It is anticipated that TriKEs will be a therapeutic option for a much larger portion of the cancer population at a fraction of the cost. TriKEs are an antibody platform that can be tailored to treat any form of cancer, liquid or solid tumors.

The TriKE platform focuses on Natural Killer (NK) cells, a type of white blood cell, which plays a major role in the rejection of tumor and virally infected cells. NK cells are an important component of the innate immune system and are critical in killing cancer cells.

The TriKE IND (OXS 3550) will focus on AML, the most common form of adult leukemia with 21,000 new cases expected in 2017 alone (American Cancer Society). These patients will require frontline therapy, usually chemotherapy including cytarabine and an anthracycline, a therapy that has not changed in over 40 years. Also, about half will have relapses and require alternative therapies. In addition, about 13,000 new cases of myelodysplastic syndrome (MDS) are diagnosed each year and there are minimal treatment options (Siegel et al, 2014). At a minimum, OXS-3550 can be expected to serve as a relatively safe, inexpensive, and easy to use therapy for resistant/relapsing AML. From a biologic standpoint, it could also be combined with chemotherapy as frontline therapy.

The University of Minnesota’s Deputy Director of the Masonic Cancer Center, Dr. Jeff Miller said, "We have focused on NK cell therapy for the past 20 years at the University of Minnesota Masonic Cancer Center. While promising, limitations of NK cell therapy include their lack of specificity and the fact that they may be suppressed by the tumor microenvironment. The design of the TriKE is intended to overcome both limitations by making NK cells antigen specific and providing IL-15 as an important activation co-stimulus."

GT Biopharma Chief Medical officer (CMO) Dr. Raymond Urbanski said, "Cancer treatment continues to move towards immunotherapy and the TriKE platform is a powerful new approach. It is the protein version of CAR-T without the excessive resource demands, expense and risk. Our current TriKE, OXS-3550, can be given as a convenient IV infusion. The commercial IND allows us to establish the safety of the TriKE which can then be administered on an outpatient basis."

GT Biopharma Chief Executive Officer (CEO) Dr. Kathleen Clarence-Smith said, "TriKEs hold great promise in treating a number of liquid and possibly solid tumors; the IND transfer to GT Biopharma will allow for faster development and earlier delivery to patients who are in great need of better therapies."

GT Biopharma Executive Chairman Anthony J. Cataldo said, "During 2017 we have continued to accomplish our goals. This is another major milestone for our shareholders. We are continuing with our stated efforts to up-list to NASDAQ."

About the TriKE: TriKE CD16/IL15/CD33 focuses on NK cell cancer-killing activity which is expected to be increased by bringing the NK cells in close proximity to the cancer cells. This is achieved by "engagers" (linkers) that bind to CD16 on the surface of NK cells and bind specific proteins (such as CD33) on the surface of cancer cells, thus linking the NK cell to the cancer cell. The inclusion of a modified Interleukin-15 (IL-15), a peptide that activates NK cells, in the "engager" further increases NK cancer-cell killing capabilities and improves their function in the tumor microenvironment (Vallera et al,2016). The TriKE platform consists of "engagers" to which a modified IL-15 has been added.

At AACR (Free AACR Whitepaper) Special Conference on Tumor Immunology and Immunotherapy took place October 1-4, 2017 in Boston, MA, Anaeropharma has presented its new research outcomes regarding cancer immunotherapy titled “Anti-PD-1 antibody scFv producing recombinant Bifidobacterium exerts antitumor effect in a larger fraction of the treated mice comparing to full length anti-PD-1 antibody” (Press release, Anaeropharma Science, OCT 24, 2017, View Source [SID1234521147])

On October 24, 2017 Alligator Bioscience (Nasdaq Stockholm: ATORX), a biotechnology company developing antibody-based pharmaceuticals for tumor-directed immunotherapy and Aptevo Therapeutics Inc. (Nasdaq: APVO), a biotechnology company focused on developing novel immuno-oncology and hematology therapeutics, reported further details of the companies’ collaboration on ALG.APV-527, a bispecific antibody targeting 4-1BB and a tumor antigen, now identified as 5T4, which is found on various types of cancer cells (Press release, Alligator Bioscience, OCT 24, 2017, View Source [SID1234538684]).

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5T4 is a protein predominantly expressed on tumor cells. It is present at very low levels or not at all in normal tissue. This enables the immune-activating effect of ALG.APV-527 to be targeted specifically to the tumor and not against normal tissue, the goal being effective tumor-directed immune activation with minimal side effects. The 5T4 tumor antigen is present on a number of different solid tumors, including breast, cervical, non-small-cell-lung, prostate, renal, gastric, colorectal and bladder cancers, indicating that ALG.APV-527 may be used for the treatment of several different types of cancer.

"The fact that 5T4 is selectively expressed on tumor cells in many different cancer indications, but in very low levels in normal tissue, makes it a very attractive target for tumor-directed immunotherapy," said Professor Peter Stern, Manchester University, UK.

By combining a tumor-binding and an immunomodulatory antibody in one molecule, Alligator and Aptevo have created a drug candidate whose effect is localized to the tumor area, activating the tumor-specific immune cells present there.

About Dr. Peter Stern
Professor Peter Stern, University of Manchester, United Kingdom, advisor to the joint venture, discovered the 5T4 antigen in 1988. He is an expert in tumor-associated antigens and virus-associated tumors. Professor Stern’s research has contributed substantially to the development of both cancer vaccines and antibody-based drugs for cancer treatment.

About ALG.APV-527
ALG.APV-527 is a bispecific antibody (4-1BB x 5T4) intended for tumor-directed treatment of solid cancers. The ALG.APV-527 antibody consists of two parts, one part activating tumor-specific T cells through the co-stimulatory receptor 4-1BB (CD137), the other part binding to the 5T4 protein expressed on the surface of tumor cells.

On October 24, 2017 Asana BioSciences, LLC, an oncology focused, clinical stage biopharmaceutical company, reported that it will present updates regarding three of its lead molecules at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) to be held in Philadelphia, PA, October 26-30, 2017 (Press release, Asana BioSciences, OCT 24, 2017, View Source [SID1234521148]).

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“The presentations will highlight the well differentiated profile of our clinical and preclinical programs, including first disclosure on our next clinical candidate ASN007, a potent ERK1/2 inhibitor.”
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“We are very pleased with the progress made in advancing our oncology portfolio,” said Sandeep Gupta, PhD, Founder, President and Chief Executive Officer at Asana BioSciences. “The presentations will highlight the well differentiated profile of our clinical and preclinical programs, including first disclosure on our next clinical candidate ASN007, a potent ERK1/2 inhibitor.”

The presentation details are as follows:

1. A Phase 1 PK/PD study of ASN003, a novel, highly selective BRAF and PI3K dual inhibitor, in patients with advanced solid tumors.

Authors: Drew Rasco1, Nehal Lakhani2, Ryan Sullivan3, Monica Mita4, Jaimini Shah5, Helena Usansky5, Sanjeeva Reddy5, Niranjan Rao5, Louis J. Denis5, Anthony Tolcher1, Keith Flaherty3. 1START San Antonio, San Antonio, TX; 2START Midwest, Grand Rapids, MI; 3Mass Gen Hosp CC, Boston, MA; 4Cedars-Sinai Medical Center, Los Angeles, CA; 5Asana BioSciences.
Session: PO.B21 – Therapeutic Agents: Small-Molecule Kinase Inhibitors
Poster # B 147; Hall E
Date/Time: Sunday, October 29, 2017 at 12:30pm – 4:00pm EDT

2. ASN007, a novel oral ERK1/2 inhibitor, shows robust antitumor activity in RAS mutant cancer models.

Authors: Sanjeeva Reddy, Dhanalakshmi Sivanandhan, Purushottam Dewang, Niranjan Rao, Roger A. Smith and Scott Thompson.
Session: PO.B21 – Therapeutic Agents: Small-Molecule Kinase Inhibitors
Poster # B 150; Hall E
Date/Time: Sunday, October 29, 2017 at 12:30pm – 4:00pm EDT

3. ASN004, a novel 5T4-targeted Dolaflexin ADC, causes complete and durable tumor regressions in a variety of tumor xenograft models.

Authors: Roger A. Smith, David J. Zammit, Sanjeeva P. Reddy.
Session: PO.B19 – Therapeutic Agents: Biological
Poster # B 109; Hall E
Date/Time: Sunday, October 29, 2017 at 12:30pm – 4:00pm EDT

ASN003 is a potent and highly selective inhibitor of both B-RAF and PI3 kinases. RAS-RAF-MEK and PI3K-AKT-mTOR are two major pathways involved in tumor cell signaling and growth. Components of these pathways are frequently mutated in a broad range of tumors. Selective BRAF inhibitors induce dimerization of RAF proteins, leading to paradoxical activation of the RAF-MEK-ERK cascade. This activation is a major limitation for the clinical use of selective RAF inhibitors, as it leads to resistance and results in side effects in the skin limiting their use in patients with BRAF mutant tumors. In addition, elevated signaling through the PI3K/AKT pathway, with or without concomitant MAPK reactivation, represents an alternative path to resistance to BRAF inhibitors. Preclinical data with ASN003, demonstrates broad anti-proliferative activity in tumor cell lines and strong tumor growth inhibition in tumor xenograft models, including BRAF inhibitor resistant models. ASN003 is currently in Phase I clinical development in patients with advanced solid tumors, including melanoma, colorectal cancer and non-small cell lung cancer. ASN003 is well tolerated and shows the potential to be developed as a monotherapy or in combination with checkpoint inhibitors or standard of care.

ASN007 is a potent inhibitor of the extracellular-signal-regulated kinases, ERK1 and ERK2 (ERK1/2), key players in the RAS/RAF/MEK (MAPK) signaling pathway. This pathway is frequently hyper-activated in a wide range of cancers through mutations in upstream targets such as BRAF, RAS and receptor tyrosine kinases. Inhibition of ERK1/2 offers a promising therapeutic strategy for these cancers, particularly those driven by RAS mutations. ASN007 shows potent anti-proliferative activity in cancer lines that are selectively driven by the MAPK-pathway, including RAS mutant cell lines. Furthermore, ASN007 demonstrates strong inhibition of tumor growth in multiple BRAF and KRAS mutant patient-derived and cell line-derived xenograft models, including those that are resistant to BRAF and MEK inhibitors. The IND-submission is planned to evaluate safety and efficacy in patients with advanced solid tumors, including BRAF and KRAS mutant cancers.

ASN004 is an Antibody Drug Conjugate (ADC) that targets the 5T4 oncofetal antigen that is expressed in a wide range of malignant tumors, while very limited expression is found in normal tissues. ASN004 demonstrates robust antitumor activity leading to complete tumor regressions in multiple human tumor xenograft models with no development of resistance to ASN004 treatment. The IND-enabling program for ASN004 is near completion and a First-in-Human Phase 1 trial is being planned in 2018.

On October 24, 2017 MabVax Therapeutics Holdings, Inc. (Nasdaq: MBVX), a clinical-stage biotechnology company with a fully human antibody discovery platform focused on the development of antibody-based products to address unmet medical needs in the treatment of cancer, reported that the Company has filed a patent application for its series of HuMab-Tn fully-human monoclonal antibodies that target the tumor associated Thomsen-nouveau (Tn) antigen that will be developed as therapeutic and diagnostic products targeting ovarian, lung and breast cancers (Press release, MabVax, OCT 24, 2017, View Source [SID1234521277]). The Tn target is a carbohydrate antigen significantly expressed on the surface of cancer cells as a result of the transformation of normal cells into cancer cells. The Tn target is present on a broad array of tumor types but not found on normal tissues. This patent represents another valuable antibody asset brought forward by MabVax and the third patent filed on the antibody portfolio created through the Company’s unique discovery platform.

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The patent application covers the recovery of anti-Tn antibodies from patients who were vaccinated against their solid tumors with a vaccine that contained the Tn antigen. The discovery of fully human antibodies directly from vaccinated cancer patients is highly unique and has advantages including a potential for greater specificity and reducing the toxicities associated with non-human antibodies. The patent application also covers the additional work done by the Company’s antibody research and development team to optimize the recovered antibodies as well as detailing the resulting positive characteristics of the antibodies selected for patenting. The newly filed patent application, if issued by the U.S. Patent Office, will provide exclusivity for these antibodies until 2038.

“The filing of this patent is an important component of our broad strategy in expanding our robust patent estate. Importantly, this filing is timely as we look to select additional product candidates to fuel our pipeline that have the potential to address significant unmet therapeutic needs,” stated David Hansen, MabVax’s President and Chief Executive Officer.

The Company has demonstrated its ability to translate these discoveries through preclinical development and into clinical development with its HuMab-5B1 program, currently being evaluated in Phase 1 clinical trials as a therapeutic agent, an immunoPET diagnostic agent, and as a radioimmunotherapy (“RIT”). The Company envisions that the HuMab-Tn antibody portfolio has similar applicability, including as a bi-specific antibody, as an antibody conjugated with a payload to form an antibody drug conjugate (“ADC”), with a radionuclide as an immunoPET imaging agent or with a radionuclide as a RIT product.